Previous Project 1 developed new approaches for breast cancer treatment using lipidic nanoparticle drugs (nanoliposomes/nLs) and immunoliposomes (ILs). Research advances included: new and robust technologies for drug loading and stabilization, resulting in novel """"""""nanoliposome"""""""" drugs;and immunoliposomes against HER2 and EGFR. These discoveries have led to the translation of four novel therapeutic agents: 1) Anti-HER2 immunoliposome doxorubicin (NSC701315, AP49) was GMP manufactured and licensed to industry;2) Anti-EGF;R immunoliposome doxorubicin) was GMP manufactured and has entered a Phase I trial at Univ. Basel (Switzerland);3) Nanoliposomal CPT-11 (PEP02) completed an initial Phase I trial and continues in Phase l/ll studies in Asia and Europe;and 4) Nanoliposomal vinorelbine is in Phase I trials in Taiwan. Previous Project 6 has discovered new phage antibodies against specific breast cancer phenotypes, including promising scFv that specifically bind and internalize in basallike/ basaloid cancers. We now hypothesize that lipidic nanoparticle agents can be developed against aggressive breast cancer phenotypes for which standard treatment is inadequate, especially basal-like tumors with their asssociated cancer stem cell characteristics. These poor prognosis tumors, typically hormone receptor(-) and HER2(-), lack effective targeted therapies and appear to have distinct chemotherapy response profiles. We will construct novel liposome-based nanoparticles encapsulating potent anti-basaloid compounds. We will also link these to basaloid-specific and internalizing mAb fragments to create immunoliposomes for targeted delivery. These will target EGFR, a current marker of basal-like tumors, as well as new basaloid-associated antigens/receptors. Further preclinical studies will prioritize the most promising nanoparticle agents from this pipeline. Finally, we will utilize our proven strategies to translate the most promising nanoparticle agents for the treatment of basal-like tumors, as these represent one of the highest unmet clinical needs in breast cancer treatment. Approaches developed in previous Projects 1&6 will be combined to complete the following four aims:
Aim 1. Construct novel liposome-based nanoparticle drugs to treat basal-like breast cancers.
Aim 2. Develop immunoliposomes optimized for targeted drug delivery in basal-like breast cancers.
Aim 3. Evaluate in vitro and in vivo efficacy of nLs and ILs in basal-like tumor models.
Aim 4. Translate novel lipidic nanoparticle drugs to clinical trials.
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